Diabetes mellitus type I, or insulin-dependent diabetes, results from a genetically conferred vulnerability that causes a primary deficiency of insulin. This deficiency of insulin is believed to be the consequence of destruction of a specialized population of cells that produce insulin in the body, i.e., pancreatic .beta.-cells. An autoimmune process may also contribute to .beta.-cell damage. As a consequence of insulin lack (and glucagon excess) , glucose production is augmented, and the efficiency of peripheral glucose use is reduced until a new equilibrium between these processes is reached at a very high plasma glucose level. Because of the high plasma glucose levels, the filtered load of glucose exceeds the renal tubular capacity for reabsorption. Glucose therefore is excreted in the urine in large quantities, causing, by its osmotic effect, increased excretion of water and salts and frequent urination. The goal of insulin treatment is to systemically lower plasma levels of glucose, free fatty acids, and ketoacids to normal and reduce urine nitrogen losses. This result is achieved by direct actions of insulin and also by diminishing the secretion of the insulin antagonist glucagon.
Another more common form of diabetes mellitus, non insulin-dependent or type II, often is associated with obesity. In this disease, there appears to be both a deficit of insulin production (Weir et al., 1982, Amer. Jour. Med. 73:461) in combination with a resistance to the action of insulin on major target tissues. The locus of resistance is distal to the insulin receptor binding site, but defects in receptor tyrosine kinase activity, glucose transport, and activities of insulin-sensitive enzymes have been found. In addition, there is a derangement in .beta.-cell recognition of glucose as a stimulus, so that first phase insulin secretion is lost, though a delayed release does occur. Treatment of type II diabetes does not normally require insulin administration. Caloric regulation, weight reduction if obesity is present, and use of sulfonylurea drugs simultaneously improve tissue responsiveness to endogenous insulin and .beta.-cell responsiveness to glucose. In late stages, insulin administration is usually required.
Insulin excess is usually caused by tumors of the .beta.-cells. The cardinal manifestation is a low plasma glucose level in the fasting state. With chronic insulin excess and persistent hypoglycemia, disturbed central nervous system function results in bizarre behavior, defects in cerebration, loss of consciousness, or convulsions. Removal of the tumor may cure the condition. Alternatively, drugs that inhibit insulin secretion may ameliorate the condition.
It is an object of the invention to provide a nucleic acid sequence encoding a novel transcriptional activator that is present in certain pancreatic cell populations, and the encoded transcriptional activator.
Another object of the invention is to provide an in vitro method for producing a desired protein using the novel transcriptional activator to activate transcription of the gene encoding the desired protein.
Yet another object of the invention is to provide methods of treating Diabetes mellitus type I, type II, or diseases in which insulin is produced in excess.
Another object of the invention is to provide a transgenic mouse model for diabetes, in which expression of the novel transcriptional activator is altered.
These and further objects of the invention will be apparent for one skilled in the art.